Abstract
Ontogeny of platelet serotonin (5-hydroxytryptamine, 5-HT) during the first year of life was examined in newborns and infants. The effects of in utero exposure to selective serotonin reuptake inhibitors (SSRI, including fluoxetine, sertraline, and citalopram) were examined by comparing cord blood 5-HT levels in exposed and unexposed newborns. Heritability was assessed by correlation of the platelet 5-HT values observed for mother-infant pairs. No age effect was observed in 1–49 wk-old infants (r = 0.13, p = 0.49) and mean platelet 5-HT levels in infants (241 ± 102 ng/mL, n = 33; 615 ± 320 ng/109 platelets, n = 32) were similar to those reported for older children and adults. However, significantly lower blood 5-HT levels were observed in newborns (81.3 ± 32.5 ng/mL, n = 16, p < 0.0001; 297 ± 101 ng/109 platelets, n = 11, p = 0.0007) compared with the 1–49 wk-old infants. The mean cord blood 5-HT concentra tions in newborns exposed in utero to SSRI (n = 8) were substantially lower than that seen in unexposed (n = 16) new borns (20.6 ± 14.4 versus. 81.3 ± 32.5 ng/mL, p = 0.0001; 90.7 ± 55.4 versus. 297 ± 101 ng/109 platelets, p = 0.0005). Platelet serotonin levels (ng/109 platelets) in mother-child pairs (n = 32) were significantly correlated (r = 0.415, p = 0.018). The results indicate that, although platelet 5-HT is low at birth, values quickly increase and stabilize at near-adult levels by 1 mo of age. Gestational exposure to SSRI appears to substantially reduce platelet 5-HT uptake in the fetus, strongly suggesting that such exposure has important physiologic effects. The observed mother-infant correlation agrees with a previous report of high heritability in a large adult population.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Abbreviations
- 5-HT:
-
5-hydroxytryptamine
- QTL:
-
quantitative trait loci
- SSRI:
-
selective serotonin reuptake inhibitor
References
De Clerck FF, Janssen PA 1990 Amplification mechanisms in platelet activation and arterial thrombosis. J Hypertens Suppl 8:S87–S93.
MacLean MR 1999 Pulmonary hypertension, anorexigens and 5-HT: pharmacological synergism in action? Trends Pharmacol Sci 20: 490–495.
Buss LJ, Lund J, Bechgaard E, Sondergaard I 1970 Inhibition of 5-HT uptake into platelet in mice treated chronically with chorimipramine and femoxetine. Psychopharmacology (Berl) 64: 149–153.
Fuller RW, Wong DT 1990 Serotonin uptake and serotonin uptake inhibition. Ann N Y Acad Sci 600: 68–80.
Karege F, Widmer J, Bovier P, Gaillard J 1994 Platelet serotonin and plasma tryptophan in depressed patients: effect of drug treatment and clinical outcome. Neuropsychopharmacology 10: 207–214.
Anderson GM 2002 Genetics of childhood disorders: XLV. Autism, part 4: serotonin in autism. J Am Acad Child Adolesc Psychiatry 41: 1513–1516.
Mulder E, Anderson GM, Kema I, de Bildt A, van Lang NDJ, den Boer JA, Minderaa RB 2004 Platelet serotonin in pervasive developmental disorders and mental retardation. J Am Acad Child Adolesc Psychiatry 43: 491–499.
Inestrosa NC, Alarcon R, Arriagada J, Donoso A, Alvarez J 1993 Platelets of Alzheimer patients: increased counts and subnormal uptake and accumulation of 14C5-hydroxytryptamine. Neurosci Lett 163: 8–10.
Epperson CN, Anderson GM, McDougle CJ 1997 Sertraline and breastfeeding. N Engl J Med 336: 1189–1190.
Epperson CN, Czarkowski KA, Ward-O'Brien D, Weiss E, Gueorguieva R, Jatlow P, Anderson GM 2001 Maternal sertraline treatment and serotonin transport in breast-feeding mother-infant pairs. Am J Psychiatry 158: 1631–1637.
Epperson CN, Jatlow PI, Czarkowski K, Anderson GM 2003 Maternal fluoxetine treatment in the postpartum period: effects on platelet serotonin and plasma drug levels in breastfeeding mother-infant pairs. Pediatrics 112:e425–e429.
Lesch KP, Wolozin BL, Murphy DL, Reiderer P 1993 Primary structure of the human platelet serotonin uptake site: identity with the brain serotonin transporter. J Neurochem 60: 2319–2322.
Rudnick G, Humphreys CJ 1992 Platelet serotonin transporter. Methods Enzymol 215: 213–224.
Buznikov GA, Lambert HW, Lauder JM 2001 Serotonin and serotonin-like substances as regulators of early embryogenesis and morphogenesis. Cell Tissue Res 305: 177–186.
Moiseiwitsch JR, Lauder JM 1995 Serotonin regulates mouse cranial neural crest migration. Proc Natl Acad Sci U S A 92: 7182–7186.
Lauder JM 1993 Neurotransmitters as growth regulatory signals: role of receptors and second messages. Trends Neurosci 16: 233–240.
Lesch KP 2001 Variation of serotonergic gene expression: neurodevelopment and the complexity of response to psychopharmacological drugs. Eur Neuropsychopharmacol 11: 457–474.
Whitaker-Azmitia PM, Druse M, Walker P, Lauder JM 1996 Serotonin as a developmental signal. Behav Brain Res 73: 19–29.
Bal-Klara A, Bird MM 1990 The effects of various antidepressant drugs on the fine-structure of neurons of the cingulate cortex in culture. Neuroscience 37: 685–692.
Vorhees CV, Acuff-Smith KD, Schilling MA, Fisher JE, Moram MS, Buelke-Sam J 1994 A developmental neurotoxicity evaluation of the effects of prenatal exposure to fluoxetine in rats. Fundam Appl Toxicol 23: 194–205.
Laine K, Heikkinen T, Ekblad U, Kero P 2003 Effects of exposure to selective serotonin reuptake inhibitors during pregnancy on serotonergic symptoms in newborns and cord blood monoamine and prolactin concentrations. Arch Gen Psychiatry 60: 720–726.
Oberlander TF, Eckstein Grunau R, Fitzgerald C, Ellwood AL, Misri S, Rurak D, Riggs KW 2002 Prolonged prenatal psychotropic medication exposure alters neonatal acute pain response. Pediatr Res 51: 443–453.
Suri R, Stowe ZN, Hendrick V, Hostetter A, Widawski M, Altshuler LL 2002 Estimates of nursing infant daily dose of fluoxetine through breast milk. Biol Psychiatry 52: 446–451.
Ober C, Abney M, McPeek MS 2001 The genetic dissection of complex traits in a founder population. Am J Hum Genet 69: 1068–1079.
Abney M, McPeek MS, Ober C 2001 Broad and narrow heritabilities of quantitative traits in a founder population. Am J Hum Genet 68: 1302–1307.
Anderson GM, Feibel FC, Cohen DJ 1987 Determination of serotonin in whole blood, platelet-rich plasma, platelet-poor plasma and plasma ultrafiltrate. Life Sci 40: 1063–1070.
Tsao CH, Green D, Schultz K 1976 Function and ultrastructure of platelets of neonates: enhanced ristocetin aggregation of neonatal platelets. Br J Hematol 32: 225–233.
Mashige F, Matsushima Y, Kanazawa H, Sakuma I, Takai N, Bessho F, Ohkubo A 1996 Acidic catecholamine metabolites and 5-hydroxyindoleacetic acid in urine: the influence of diet. Ann Clin Biochem 33: 43–49.
Anderson GM, Stevenson JM, Cohen DJ 1987 Steady-state model for plasma free and platelet serotonin in man. Life Sci 41: 1777–1785.
Gershon MD 1998 The Second Brain. Harper-Collins, New York
Mulder EJ, Anderson GM, Kema IP, Minderaa RB 2002 Reactivity of serotonin in whole blood. Biol Psychiatry 51: 266–268.
Berman JL, Justice P, Hsia DY 1965 The metabolism of 5-hydroxytryptamine (serotonin) in the newborn. J Pediatr 67: 603–608.
Hazra M, Benson S, Sandler M 1965 Blood 5-hydroxytryptamine levels in the newborn. Arch Dis Child 40: 513–515.
Tu J, Wong CY 1976 Serotonin metabolism in normal and abnormal infants during the perinatal period. Biol Neonate 29: 187–193.
Flachaire E, Beney C, Berthier A, Salandre J, Quincy C, Renaud B 1990 Determination of reference values for serotonin concentration in platelets of healthy newborns, children, adults and elderly subjects by HPLC with electrochemical detection. Clin Chem 36: 2117–2120.
De Villard R, Flachaire E, Laujin A, Maillet J, Revol O, Charles S, Mamelle JC, Renaud B, Quincy C 1991 Platelet serotonin concentration in children under 5 years of age. Pediatrie 46: 813–816.
McBride PA, Anderson GM, Hertzig ME, Snow ME, Thompson SM, Khait VD, Shapiro T, Cohen DJ 1998 Effects of diagnosis, race, and puberty status on platelet serotonin levels in autism and mental retardation. J Am Acad Child Adolesc Psychiatry 37: 767–779.
Anderson GM, Bennett AJ, Weld KP, Pushkas JG, Ocame DM, Higley JD 2002 Serotonin in cisternal cerebrospinal fluid of the rhesus monkeys: basal levels and effects of sertraline administration. Psychopharmcology 161: 95–99.
Weiss L, Veenstra-VanderWeele J, Abney M, Dytch H, McPeek MS, Cheng S, Cook E, Pober C 2003 Genome-wide association mapping in a founder population identifies ITGB3 as a QTL for whole blood serotonin levels. Am J Hum Genet 73( suppl 5): 178.
Zeskind PS, Stephens LE 2004 Maternal selective serotonin reuptake inhibitor use during pregnancy and newborn behavior. Pediatrics 113: 368–375.
Acknowledgements
The authors thank the women and infants who took part in this study. We also thank the obstetricians and midwives of the County Obstetrics and Gynecology practice for their critical efforts in recruiting the participation of SSRI-unexposed infants.
Author information
Authors and Affiliations
Corresponding author
Additional information
Portions of the research were supported by grants from the National Institute of Mental Health [#01830-K23 (C.N.E.), #MH-30929 (G.M.A.)] and the Pfizer and Eli Lily companies (C.N.E.).
Rights and permissions
About this article
Cite this article
Anderson, G., Czarkowski, K., Ravski, N. et al. Platelet Serotonin in Newborns and Infants: Ontogeny, Heritability, and Effect of In Utero Exposure to Selective Serotonin Reuptake Inhibitors. Pediatr Res 56, 418–422 (2004). https://doi.org/10.1203/01.PDR.0000136278.23672.A0
Received:
Accepted:
Issue date:
DOI: https://doi.org/10.1203/01.PDR.0000136278.23672.A0
This article is cited by
-
Systematic review of studies using platelet serotonin content to assess bioeffect of serotonin reuptake inhibitors at the serotonin transporter
Psychopharmacology (2023)
-
Association between cord blood metabolites in tryptophan pathway and childhood risk of autism spectrum disorder and attention-deficit hyperactivity disorder
Translational Psychiatry (2022)
-
Severity of neonatal opioid withdrawal syndrome with prenatal exposure to serotonin reuptake inhibitors
Pediatric Research (2022)
-
In Utero Exposure to Selective Serotonin Reuptake Inhibitors and Risk for Autism Spectrum Disorder
Journal of Autism and Developmental Disorders (2014)
-
Disubstituted Diaryl Diselenides Inhibit [3H]-Serotonin Uptake in Rats
Neurotoxicity Research (2009)